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Right arrow Cardiac - pharmacology

Ann Thorac Surg 2003;76:1252-1258
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Intra-myocyte ion homeostasis during ischemia-reperfusion injury: effects of pharmacologic preconditioning and controlled reperfusion

James E. Davies, MDa, Stanley B. Digerness, PhDa, Steven P. Goldberg, MDa, Cheryl R. Killingsworth, PhDa, Charles R. Katholi, PhDb, Paul S. Brookes, PhDc, William L. Holman, MDa*

a Department of Surgery, Birmingham, Alabama, USA
b Department of Medicine, Birmingham, Alabama, USA
c Department of Biostatistics, Birmingham, Alabama, USA, and Department of Pathology, Birmingham, Alabama, USA, University of Alabama at Birmingham, Birmingham, Alabama, USA

Accepted for publication April 8, 2003.

* Address reprint requests to Dr Holman, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
e-mail: wholman{at}its.uab.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: This study determines whether controlled reperfusion or diazoxide improves intramyocyte Na+ homeostasis using a porcine model of severe ischemia-reperfusion injury.

METHODS: Three groups (n = 10 pigs per group) had 75 minutes of left anterior descending artery occlusion during bypass. Group 1 had no treatment (control group), group 2 had controlled reperfusion (500 mL warm cardioplegia) (controlled reperfusion group), and group 3 had diazoxide (50 µmol/L before left anterior descending artery occlusion) (diazoxide group). Biopsies were taken from the left anterior descending artery region before ischemia and at 3, 5, and 10 minutes postreperfusion. Intra-myocyte Na+ and water contents were determined using atomic absorption spectroscopy, and Na+ concentrations were calculated.

RESULTS: Intra-myocyte Na+ increased for the diazoxide group pigs at 3-minutes postreperfusion (21.9 ± 2.9 vs 34.0 ± 3.4 µmol/mL; p = 0.02), but decreased to 19.9 ± 3.2 µmol/mL at 10 minutes postreperfusion (p = 1.0 vs baseline). At 10 minutes postreperfusion, intra-myocyte Na+ in the controlled reperfusion group was lower than baseline (22.3 ± 2.7 vs 17.2 ± 3.1 µmol/mL; p < 0.001). Intra-myocyte Na+ at 10 minutes postreperfusion for the diazoxide and controlled reperfusion groups was lower than for the control group (p < 0.05).

CONCLUSIONS: Diazoxide and controlled reperfusion improved intra-myocyte Na+ homeostasis after severe ischemia-reperfusion injury.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Ischemia-reperfusion (I-R) injury remains an important problem in cardiac surgery, especially for patients who suffer severe ischemic injury during or immediately before their operation. Perioperative myocardial ischemia and infarction may occur as a complication in all types of cardiac operations. Intraoperative myocardial ischemia can be caused by imperfect myocardial protection during cardioplegic arrest, excessive duration of cardioplegic arrest, coronary arterial spasm, embolization of the coronary arteries with gaseous or particulate matter, acute occlusion of coronary arteries (iatrogenic or due to coronary thrombosis), or preexisting coronary insufficiency (eg, perioperative infarction due to preoperative acute myocardial ischemia). The severity of an intraoperative ischemic injury is exacerbated by preexisting cardiac pathology (eg, ventricular hypertrophy and valvular heart disease).

Studies with large numbers of patients have unequivocally shown that perioperative myocardial infarction has an adverse effect on survival. In these studies, immediate survival was decreased by perioperative infarction, and long-term survival was also lower, especially in those patients who had more extensive myocardial infarction or worse preoperative myocardial function [1, 2]. In a post hoc analysis of data from a coronary artery surgery study [3], long-term survival with complicated perioperative myocardial infarction was significantly worse than with uncomplicated perioperative infarction or no perioperative infarction at all. The deleterious influence of perioperative myocardial infarction on survival persisted even when patients who died before discharge were excluded from the analysis. Based on this information, it is likely that salvaging ischemic myocardium, optimizing cardiac contractile function, and minimizing I-R arrhythmias in patients with acute perioperative myocardial ischemia will improve outcome in cardiac surgical patients.

Our laboratory is developing a new approach to managing severe myocardial I-R injury that occurs during a cardiac operation. The approach focuses on one aspect of myocardial I-R injury, namely myocyte sodium (Na+) influx and consequential loss of intra-myocyte ionic homeostasis during ischemia and early reperfusion. Na+ influx is a pivotal early event that putatively leads to myocardial calcium (Ca2+) influx, contractile dysfunction, mitochondrial Ca2+ loading with consequential damage to mitochondrial synthetic apparatus and cell death [4–7]. Loss of ionic homeostasis is an aspect of I-R injury that is amenable to treatment with novel methods, one of which is now in clinical trials (cariporide [Aventis Pharmaceuticals, Somerset, NJ], a drug that inhibits Na+-proton exchange). Pharmacological-induced preconditioning with diazoxide and controlled postischemic reperfusion are two other methods that may protect mitochondria and favorably affect intra-myocyte ion homeostasis in the setting of I-R injury [8, 9]. The long-term goal of our project is to develop a combination of treatments that additively protects myocyte ion homeostasis and thereby improves outcome from severe myocardial I-R injury that occurs during a cardiac operation. The purpose of the present study is to determine the effects of controlled reperfusion and pharmacological-induced preconditioning (ie, opening mitochondrial adenosine triphosphate-dependent potassium [K+ATP] channels) on intra-myocyte Na+ homeostasis after severe regional ischemic injury. The hypothesis tested is that each of these treatments improves intra-myocyte Na+ homeostasis after severe regional I-R injury in a clinically relevant animal model.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
The University of Alabama at Birmingham Institutional Animal Care and Use Committee approved the experimental protocols. This protocol met the requirements of the National Institutes of Health standards defined by the United States Department of Agriculture Animal Welfare Acts.

Surgical protocol
Thirty pigs of both sexes with weights of 28.6 to 59.0 kg were used in this experimental protocol study (see Fig 1). They were anesthetized with intramuscular atropine (0.4 mg/kg), tiletamine and zolazepam (4.4 mg/kg), and xylazine (4.4 mg/kg). Anesthesia was maintained with sodium pentobarbital (0.05 mg/kg/hour) by continuous infusion. Animals were given intravenous lactated Ringer's solution, and they were intubated and mechanically ventilated with 100% oxygen. Skeletal muscle paralysis was maintained with intravenous pancuronium (0.11 mg/kg) to minimize skeletal muscle contraction during shock delivery. The right carotid artery and external jugular veins were cannulated for continuous measurement of arterial blood pressure and infusion of crystalloid solutions, respectively. Arterial blood gas values and electrolyte levels were maintained within the normal range throughout the experiment.



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  		Fig 1. Experimental protocol. (Co EDTA = cobalt ethylenediaminetetraacetic acid; H K+ C.P. = high potassium cardioplegia; LAD = left anterior descending coronary artery.)

 
A median sternotomy was performed and the animals were heparinized (10,000 U initially and 5,000 U every hour during cardiopulmonary bypass). Cardiopulmonary bypass (2.2 L/min/m2 at 38°C) was initiated through the aortic and right atrial cannulations. Intra-myocyte ion measurements were made by isolated perfusion of the heart through an aortic root cannula with the extracellular marker cobalt ethylenediaminetetraacetic acid (Co-EDTA) at 37°C. The left ventricle was decompressed by a pulmonary artery vent. After the initial left ventricular biopsy, cardiopulmonary bypass flow was decreased to 1.8 L/min/m2 and the animal was cooled to 30°C.

Three groups of 10 pigs each were studied. The first group was a control group that received only the vehicle drug dimethyl sulfoxide and Co-EDTA by continuous infusion for 10 minutes at 70 mm Hg through an aortic root cannula before the left anterior descending coronary artery (LAD) occlusion. The second group received diazoxide (50 µmol/L) in dimethyl sulfoxide and Co-EDTA for an initial 10-minute dose. The third group (the controlled reperfusion group) received dimethyl sulfoxide and Co-EDTA before acute ischemia as in the control group, and then they received 500 mL of hyperkalemic, hypocalcemic blood cardioplegia solution (standard Buckberg solution) at 37°C and at 70 mm Hg aortic root pressure during initial reperfusion. The initial dose of warm cardioplegia solution was followed by normokalemic blood from the oxygenator infused into the aortic root at a pressure of 70 mm Hg.

Coronary occlusion was accomplished with a ligature around the proximal LAD for a total of 75 minutes. After the initial 45 minutes of ischemia, the aorta was cross-clamped, and a 3-minute infusion of a cold (4°C) hyperkalemic, hypocalcemic blood cardioplegia solution was started. Supplemental 1-minute cardioplegia doses were given every 15 minutes thereafter for a total of four doses of cold blood cardioplegia. The LAD occlusion was released after the third dose of cardioplegia to mimic surgical revascularization of an acutely ischemic region. After 1 hour of hypothermic cardioplegic arrest, reperfusion was initiated with a normothermic (37°C), normokalemic blood cardioplegia solution.

Five transmural biopsies (5 mm diameter by trephine drill) were taken from the left ventricle in both the LAD and left circumflex blood flow distributions for a total of ten left ventricular biopsies. The first (control) biopsy was obtained before LAD occlusion, the second was taken immediately before reperfusion after 1 hour of cardioplegic arrest, and the final three biopsies were obtained during postcardioplegia reperfusion (3, 5, and 10 minutes after initiating reperfusion). At the time of each myocardial biopsy, samples of the blood cardioplegia solution were taken for measurement of electrolyte concentrations. The electrolyte and water contents of each myocardial biopsy were analyzed by atomic absorption spectroscopy, as detailed in the following section.

Myocyte electrolyte and water content measurements
Measurements of myocardial water and electrolyte (Na+ and Ca2+) contents were made using atomic absorption spectrometry with Co-EDTA as the extracellular marker [10, 11]. Transmural biopsies of the left ventricular myocardium (5 mm diameter) were obtained after equilibrating the Co-EDTA in the plasma and interstitial space by 10 minutes of infusion. The EDTA tightly chelates cobalt ions so that the complex is nontoxic and has no discernable effect on the myocardial contractility. The technique for obtaining and analyzing the transmural cylindrical biopsies in pigs is as follows. Immediately after obtaining the biopsy, the tissue is blotted and weighed (wet weight). The biopsies are next placed in a vacuum oven at 70°C for 48 hours, removed, and weighed again (dry weight). Individual dried biopsy specimens are placed in 60 mL Teflon bottles with 0.5 mL of 6N ultrapure nitric acid (GFS Chemicals, Columbus, OH) and digested overnight at 80°C. The dissolved tissue is assayed for total calcium and cobalt contents with graphite furnace atomic absorption spectroscopy (Varian, Inc, San Fernando, CA) and are also assayed for total sodium content with flame atomic absorption spectroscopy.

Samples of aortic root blood are taken at the same time as the tissue biopsies for determination of perfusate electrolyte concentrations (Na+ and Ca2+). These blood samples are centrifuged to remove cells, then the plasma is withdrawn and de-proteinized with 10% trichloroacetic acid 1:1 (volume:volume). From the plasma concentrations and the tissue contents of cobalt (Co), interstitial water (ISW) content is calculated using the formula:

Intracellular water (ICW) content is determined by subtracting interstitial water from total water content. Interstitial electrolyte contents are calculated by the method of Scheufler and Peters [12]. This method assumes complete equilibration of the extracellular marker, Co-EDTA, with the interstitial space within the equilibration period, which we have verified experimentally. Interstitial electrolyte contents were then calculated from the expression:

where XIS is the interstitial content of an electrolyte and [X]P is the plasma concentration of that electrolyte. Intracellular electrolyte contents, XIC, are then calculated by subtracting interstitial electrolyte from total tissue electrolyte contents:

Statistical analysis
As previously described, the data for analysis is such that a repeated measures of mixed analysis of variance model is appropriate. The repeated measures are the observations over time within the individual study animal. There are three groups and four time points. For analysis purposes the covariance structure within an animal is treated as unstructured as would be done in a multivariate analysis of variance. The model contains terms for the group, the time, and the group by time interaction. Multiple comparisons made among groups at specific times and within groups over time have been adjusted for multiple comparisons using Tukey's method. The computations for the statistical models were done using the SAS PROC mixed procedure (SAS Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
The sodium concentrations at times 0, 3, 5, and 10 minutes for the LAD and circumflex regions are shown in Figures 2A and 2B. The water contents for these two regions are displayed in Figures 3A and 3B. The baseline sodium concentrations and the baseline water contents for all three groups (control, diazoxide, and controlled reperfusion group) were slightly different, but the differences were not consistent across regions and none of these differences attained statistical significance. The p values for specific comparisons between the test groups and the control group are listed in Tables 1 and 2. The Ca2+ values were not consistently different between groups and these data are not displayed. This finding is most likely due to the large store of Ca2+ in the sarcoplasmic reticulum that is measured as intra-myocyte Ca2+ and overshadows the relatively small changes that may have occurred in cytoplasmic Ca2+ during ischemia and reperfusion.



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  		Fig 2. Na+ concentration was calculated from water content and intramyocyte Na+ content and was displayed as a function of time. (A) Na- concentration-LAD distribution. (B) Na+ concentration-LCxA distribution. (CNT RPF = controlled reperfusion; LAD = left anterior descending artery; LCxA = left circumflex coronary artery; SD = standard deviation.)

 


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  		Fig 3. Intra-myocyte water content displayed as a function of time. (A) Intramyocyte water content-LAD. (B) Intramyocyte water content-LCxA. (CNT RPF = controlled reperfusion; LAD = left anterior descending artery; LCxA = left circumflex coronary artery; SD = standard deviation.)

 

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  		Table 1. Individual Group Comparisons for the Left Anterior Descending Coronary Artery Region

 

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  		Table 2. Individual Group Comparisons for Left Circumflex Region

 
The ischemic injury in the LAD distribution was more severe than in the left circumflex artery distribution due to the transient occlusion of the proximal LAD. In the LAD region, there was an acute increase of intra-myocyte Na+ concentration at 3 minutes of reperfusion in the control and diazoxide groups. The intra-myocyte Na+ concentration then decreased in the diazoxide group at 5 and 10 minutes after reperfusion, whereas the control group intra-myocyte Na+ concentration remained at the increased level. The intra-myocyte Na+ concentration in the controlled reperfusion group remained more or less constant throughout reperfusion. Thus, the test groups displayed a different pattern of changes in Na+ concentration during the period of reperfusion as compared with the control group (ie, the group-time interaction for the test groups as compared with the control group was statistically significant). Comparisons of intra-myocyte Na+ concentrations for each of the test groups at t = 10 minutes after reperfusion similarly indicate a statistically significantly lower Na+ concentration as compared with the control group (Table 1).

The intra-myocyte water contents were similar for the test groups and the control group during reperfusion, and the pattern of change in intra-myocyte water contents was similar for the three groups during reperfusion (ie, the group-time interaction for the test groups as compared with the control group was statistically insignificant). This means that the changes in the calculated value for intra-myocyte Na+ concentration cannot be attributed to changes in water content. Instead, changes in intra-myocyte Na+ were responsible for the observed differences.

Ischemia in the left circumflex coronary artery distribution was limited to the effect of hypothermic cardioplegic arrest, which is milder than ischemia due to acute coronary artery occlusion such as that in the LAD distribution. Even with a milder ischemic injury, intra-myocyte Na+ showed a statistically significant group-time interaction for the test groups as compared with the control group for the circumflex region. As was the case in the LAD distribution, the intra-myocyte Na+ concentration was higher in the control group than in the other two groups at 10 minutes after the start of reperfusion (Table 2). However, this difference did not reach statistical significance for the diazoxide group (Table 2).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
This study defined the effects of pharmacologic preconditioning with diazoxide and controlled postcardioplegia reperfusion on intra-myocyte Na+ homeostasis in a model that mimics a severe regional ischemic event that occurs during a cardiac operation. Both of the treatments (ie, controlled reperfusion and pre-ischemic dosing of diazoxide) resulted in more rapid return of intra-myocyte Na+ concentrations to baseline levels as compared with the control group. This improvement was achieved by preventing an increase in intra-myocyte Na+ concentration in the controlled reperfusion group and rapidly reversing an increase in intra-myocyte Na+ concentration in the diazoxide group during reperfusion.

The important role that acute increases in intra-myocyte calcium play in mediating myocyte necrosis is well established [13]. However, the mechanisms for excessive calcium accumulation and the reasons for failure of intra-myocyte calcium homeostasis in the setting of severe I-R injury have not been fully elucidated. One important contributor to the influx of calcium after I-R injury appears to be an antecedent acute increase in intra-myocyte Na+. This increase is partly due to activity of the Na+-proton exchanger during reperfusion as it extrudes protons generated by anaerobic metabolism. The increase of intra-myocyte Na+ stimulates activity of the sarcolemmal Na+-Ca2+ exchanger, thereby resulting in net cytoplasmic Ca2+ gain. Drugs that inhibit sodium-proton exchange diminish the uptake of Na+ and Ca2+ after myocardial I-R injury, thereby protecting the heart from necrosis, arrhythmias, and mechanical dysfunction [14–16]. The present study tested the hypothesis that two other methods for protecting the heart from I-R injury (ie, controlled postcardioplegia reperfusion and pre-ischemic treatment with the mitochondrial K+ATP channel opening drug diazoxide) improve intra-myocyte Na+ homeostasis after a severe ischemic injury. Proving this hypothesis is a crucial step in the rational design of methods that combine multiple treatments to achieve additive protection against severe I-R injury, such as perioperative myocardial infarction.

One of the first decisions in designing the present study was how to measure ion homeostasis, which is defined for the purposes of this study as changes in intra-myocyte Na+ concentration during ischemia and reperfusion. Nuclear magnetic resonance spectroscopy is impractical for an intact large animal preparation. Moreover, signals from erythrocytes make readings of intra-myocyte ions by nuclear magnetic resonance spectroscopy impossible. The use of intracellular calcium or sodium sensitive dyes is likewise impractical for obtaining transmural measurements in an intact large animal preparation. Atomic absorption spectroscopy was chosen because it permitted measurements of intra-myocyte Na+ from serial transmural left ventricular biopsies. However, there are limitations in these measurements. First, the measurement of intra-myocyte Na+ content is made indirectly by subtracting extracellular sodium content (a calculated value) from total sodium content (a measured value). Second, the intracellular Na+ concentration must be calculated from measurements of intracellular Na+ and water contents. Third, atomic absorption spectroscopy is a technique that requires a high degree of precision in execution because small errors in measurements can lead to large errors and even impossible values for intracellular Na+ content (eg, negative numbers). Fourth, the biopsy required for this analysis is relatively large. These holes in the left ventricular free wall make determinations of contractile function, cardiac isoenzymes, and reperfusion arrhythmias impossible or meaningless. Moreover, one must be careful in placing the biopsy sites to avoid coronary arterial branches or otherwise placing one site so that it affects the blood supply of subsequent biopsies. Fifth, atomic absorption spectroscopy was not able to detect changes in cytoplasmic calcium due to I-R injury. This is apparently because calcium stored in the sarcoplasmic reticulum is also measured as intracellular, and the sarcoplasmic reticulum's calcium store grossly overshadows cytoplasmic calcium in magnitude.

The findings of this study indicate that diazoxide and controlled postcardioplegia reperfusion each improve intra-myocyte Na+ homeostasis after severe I-R injury. The putative mechanisms for these two methods are different from one another, although they both involve mitochondria. Specifically, diazoxide opens mitochondrial adenosine triphosphate-dependent potassium channels. There is now considerable evidence that this protects mitochondria from acute increases in cytoplasmic calcium [17–20]. Protection of mitochondria will optimize the production of high-energy phosphates during reperfusion, which will improve the chances for myocyte survival. Note that diazoxide itself has no direct effect on the influx of Na+ or Ca2+ during ischemia and reperfusion, and in the present study Na+ increased dramatically at 3 minutes after reperfusion, but rapidly decreased to baseline values.

Inducing a period of asystole with warm cardioplegia solution during early reperfusion is the mechanism postulated for improving intra-myocyte ion homeostasis by controlled postcardioplegia reperfusion. Electrical activity during ischemia and reperfusion, especially ventricular fibrillation, increases the influx of Na+ during ischemia and slows the recovery of myocyte high-energy phosphates during reperfusion in an isolated crystalloid-perfused rat heart model [21]. Preventing electromechanical activity during early reperfusion is also cardioprotective by sparing high-energy phosphates for adenosine triphosphate-dependent sarcolemmal ion exchangers that are active in restoring ionic homeostasis during reperfusion (eg, Na+-K+ adenosine triphosphatase) [22]

Controlled postcardioplegia reperfusion has been extensively studied [23–25] and is clinically used widespread. It is unique in that it can be used after an ischemic event to diminish reperfusion injury. If one mechanism for the benefits of controlled reperfusion is an improvement in ion homeostasis after I-R injury, the addition of controlled reperfusion to other methods that improve postischemic ion homeostasis by different mechanisms (eg, Na+-proton exchange inhibition or pharmacologic preconditioning) is likely to supplement the protection from the other methods.

The notion of simultaneously using more than one method to protect the heart from I-R injury is not new. However, studies looking for additive protection have not been performed in a surgical model, and there are no studies that included controlled reperfusion as one of the methods. Moreover, the results of studies thus far have yielded conflicting results with some studies supporting [8, 26–31] and others refuting [32–34] the potential for additive benefits from using multiple methods for myocardial protection (eg, ischemic preconditioning and Na+-proton exchange inhibition).

Our laboratory has produced evidence that three methods for myocardial protection (ie, pharmacological preconditioning, Na+-proton exchange inhibition, and controlled reperfusion) each decrease the gain in intra-myocyte Na+ that otherwise occurs with I-R injury. Moreover, the ability to use two of the methods to act additively was demonstrated in an isolated rat heart model of severe ischemia [8]. The present study used a blood-perfused intact heart model of severe regional ischemia, which showed that controlled reperfusion and pharmacologic preconditioning with diazoxide improve Na+ homeostasis after I-R injury. Currently ongoing research in our laboratory is using measurements of infarct size and regional contractile function to determine if the combination of pharmacologic preconditioning, Na+-proton exchange inhibition, and controlled reperfusion provides superior protection from severe I-R injury. Other studies are examining the effect of multiple methods for myocardial protection on mitochondrial structure and function in an effort to define the mechanism for this additive protection.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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William L. Holman
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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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